Changes In Uterine Contractility Research Articles

High glucose induced HIF-1α/TREK1 expression and myometrium relaxation during pregnancy.

The incidence of gestational diabetes mellitus (GDM) is increasing worldwide. GDM patients have a significantly higher rate of cesarean section and postpartum hemorrhage, suggesting changes in uterine contractility. TWIK-1-related potassium channel (TREK1) expressed in the pregnant uterus and its role in uterine contraction. In this study, we examined the expression of HIF-1α and TREK1 proteins in GDM uterine and investigated whether high glucose levels are involved in the regulation of human uterine smooth muscle cells (HUSMCs) contraction through TREK1, and verified the role of HIF-1α in this process. Compared the uterine contractility between GDM and normal patients undergoing elective lower segment cesarean section. The HUSMCs were divided into normal glucose group, high glucose group, normal glucose with CoCl2 group, CoCl2 with echinomycin/L-Methionine group, and high glucose with echinomycin/L-Methionine group; Compare the cell contractility of each group. Compared the expression of hypoxia-inducible factor-1α (HIF-1α) and TREK1 protein in each group. The contractility of human uterine strips induced by both KCl and oxytocin was significantly lower in patients with GDM compared with that in normal individuals, with increased TREK1 and HIF-1α protein expression. The contractility of cultured HUSMCs was significantly decreased under high glucose levels, which was consistent with increased expression of HIF-1α and TREK1 proteins. The contractility of HUSMCs was decreased when hypoxia was induced by CoCl2 and increased when hypoxia was inhibited by echinomycin. The TREK1 inhibitor L-methionine also recovered the decreased contractility of HUSMCs under high glucose levels or hypoxia. The high glucose levels decreased the contractility of the myometrium, and increased expression of HIF-1a and TREK1 proteins play a role in changes in uterus contractility.

Identification of a novel distension-evoked motility pattern in the mouse uterus.

The dynamic changes in uterine contractility in response to distension are incompletely understood. Rhythmic, propagating contractions of nonpregnant uterine smooth muscle occur in the absence of nerve activity (i.e., myogenic), events that decline during pregnancy and reemerge at parturition. We therefore sought to determine how myogenic contractions of the nonpregnant uterus are affected by distension, which might provide mechanistic clues underlying distension-associated uterine conditions such as preterm birth. Uteri isolated from nulliparous adult female mice in proestrus were video imaged to generate spatiotemporal maps, and myoelectrical activity simultaneously recorded using extracellular suction electrodes. Motility patterns were examined under basal conditions and following ramped intraluminal distension with fluid to 5 and 10 cmH2O. Intraluminal distension caused pressure-dependent changes in the frequency, amplitude, propagation speed, and directionality of uterine contractions, which reversed upon pressure release. Altered burst durations of underlying smooth muscle myoelectric events were concurrently observed, although action potential spike intervals were unchanged. Voltage-gated sodium channel blockade [tetrodotoxin (TTX); 0.6 µM] attenuated both the amplitude of contractions and burst duration of action potentials, whereas all activity was abolished by L-type calcium channel blockade (nifedipine; 1 µM). These data suggest that myogenic motility patterns of the nonpregnant mouse uterus are sensitive to changes in intraluminal pressure and, at high pressures, may be modulated by voltage-gated sodium channel activity. Future studies may investigate whether similar distension-evoked changes occur in the pregnant uterus and the possible pathophysiological role of such activity in the development of preterm birth.

Enhanced Uterine Contractility and Stillbirth in Mice Lacking G Protein-Coupled Receptor Kinase 6 (GRK6): Implications for Oxytocin Receptor Desensitization.

Oxytocin is a potent uterotonic agent and is used clinically for induction and augmentation of labor, as well as for prevention and treatment of postpartum hemorrhage. Oxytocin increases uterine contractility by activating the oxytocin receptor (OXTR), a member of the G protein-coupled receptor family, which is prone to molecular desensitization. After oxytocin binding, the OXTR is phosphorylated by a member of the G protein-coupled receptor kinase (GRK) family, which allows for recruitment of β-arrestin, receptor internalization, and desensitization. According to previous in vitro analyses, desensitization of calcium signaling by the OXTR is mediated by GRK6. The objective of this study was to determine the role of GRK6 in mediating uterine contractility. Here, we demonstrate that uterine GRK6 levels increase in pregnancy and using a telemetry device to measure changes in uterine contractility in live mice during labor, show that mice lacking GRK6 produce a phenotype of enhanced uterine contractility during both spontaneous and oxytocin-induced labor compared with wild-type or GRK5 knockout mice. In addition, the observed enhanced contractility was associated with high rates of term stillbirth. Lastly, using a heterologous in vitro model, we show that β-arrestin recruitment to the OXTR, which is necessary for homologous OXTR desensitization, is dependent on GRK6. Our findings suggest that GRK6-mediated OXTR desensitization in labor is necessary for normal uterine contractile patterns and optimal fetal outcome.

Kv7 and Kv11 channels in myometrial regulation

Ion channels play a key role in defining myometrial contractility. Modulation of ion channel populations is proposed to underpin gestational changes in uterine contractility associated with the transition from uterine quiescence to active labour. Of the myriad ion channels present in the uterus, this article will focus upon potassium channels encoded by the KCNQ genes and ether-à-go-go-related (ERG) genes. Voltage-gated potassium channels encoded by KCNQ and ERG (termed Kv7 and Kv11, respectively) are accepted as major determinants of neuronal excitability and the duration of the cardiac action potential. However, there is now growing appreciation that these ion channels have a major functional impact in vascular and non-vascular smooth muscle. Moreover, Kv7 channels may be potential therapeutic targets for the treatment of preterm labour.

Relationship between gene expression and function of uterotonic systems in the rat during gestation, uterine activation and both term and preterm labour

We have documented gestation- and labour- (preterm and term) dependent changes in expression of genes encoding contraction associated proteins in the rat uterus and correlated these changes with various parameters of uterine contractility. The data demonstrate increased expression of contractile agonist systems concurrent with decreased expression of relaxant systems after gestational day 20. Significant increases in expression of oxytocin (OT), its receptor (OTR), prostaglandin (PG) H synthase isoform 1 (PGHS-1) and PGF(2alpha) receptor (FP) occurred first, followed by increases in PGHS-2, connexin-43, endothelin-1 (ET-1) and the ET-1 receptor isoform ET(A). Expression of OTR and FP was significantly reduced during mid-gestation compared to non-pregnant animals. Expression of inducible nitric oxide synthase (iNOS) increased significantly during pregnancy then decreased concurrently with the increase in OTR and FP. Functional changes in uterine contractility accompany changes in gene expression. OT was the most potent contractile stimulant. Sensitivity of uterine strips to OT was reduced in early and mid-pregnancy then increased at uterine activation. Progesterone antagonist-induced preterm labour caused changes similar to those at normal term. Comparison of mRNA transcripts in separated endometrium and myometrium suggested that the endometrium is an important regulator of myometrial contractility, analogous to the relationship between endothelium and vascular smooth muscle. This novel combination of functional and genetic expression analyses provides new insight into the physiology of parturition.

Uterine contractility in response to different prostaglandins: results from extracorporeally perfused non-pregnant swine uteri

Prostaglandins (PGs) are important stimulators of uterine contractility. Limited data are available at present on the effects of different PGs on uterine contractility, measured using intraluminal pressure changes in the complete uterus. The goal of this study was to assess dynamic changes in uterine contractility and peristalsis in response to PGs in comparison with the effects of oxytocin administration. An extracorporeal perfusion model of swine uteri was used, which keeps the uterus in a functional condition, and is appropriate for the study of physiological questions. Oxytocin- and PG-induced uterine contractility and peristalsis were assessed using an intrauterine double-chip microcatheter. A dose-dependent increase in intrauterine pressure (IUP) in the isthmus uteri (P < 0.001) and the corpus uteri (P < 0.001) was observed after the administration of PGF(2alpha) and oxytocin, which reached a plateau after further stimulation. A dose-dependent increase in IUP in the isthmus uteri (P < 0.001) and the corpus uteri (P < 0.001) was also observed after the administration of PGE(1) and PGE(2), with a plateau in IUP in the middle-concentration range and a decrease in the course of further stimulation. PGE(2) caused significantly more contractions starting in the corpus uteri and moving to the isthmus uteri (P = 0.008). The direction of most contractions caused by PGE(1), PGE(2) and oxytocin differed from that of PGF(2alpha). This study demonstrates that the PGs tested modulate contractility in non-pregnant swine uteri in a characteristic way, resulting in different contractility patterns.

Characteristics of bovine early puerperal uterine contractility recorded under farm conditions

A non-invasive, digital technique was used to measure and quantify intrauterine pressure (IUP) changes in early postpartum dairy cows kept under farm conditions in order to document physiological changes in uterine contractility after uncomplicated calvings. In addition, possible relationships between characteristics of uterine contractility and blood ionized calcium (Ca 2+)-concentrations were investigated. Recordings of uterine contractility were made by using a transcervically inserted open tip catheter in 12 healthy cows during their first 48 h after calving. The IUP recording technique appeared easily applicable under farm conditions. Although mean frequency (FREQ), amplitude (AMP) and area under the curve (AUC) of the myometrial contractions significantly decreased due to time, untreated early postpartum cows showed a high variability in characteristics of uterine contractility. There was no correlation between blood Ca 2+-concentrations and any of the contractility parameters.

Postpartum intrauterine pressure studies of the uterotonic effect of oral misoprostol and intramuscular syntometrine

Objectives To investigate the effect of oral misoprostol in dosages varying from 200 μg to 800 μg on postpartum uterine contractility and to establish their side effects. Design A prospective descriptive study. Participants Fifty-seven women who delivered vaginally after spontaneous labours not requiring augmentation. Methods Within 5 minutes of delivery of the placenta, a calibrated Gaeltec catheter with an intrauterine pressure transducer at its tip was inserted transcervically into the uterine cavity. Cumulative uterine activity was recorded for 30 minutes in each woman before administering the oral misoprostol tablets and continued for a further 90 minutes after its administration. Thus each woman acted as her own control regarding changes in uterine contractility. Uterine activity was recorded on a Sonicaid Meridian fetal monitor, which measures active contraction area automatically. The incidence of side effects was also recorded. Results There was no statistical difference ( P=0.887) in the adjusted mean difference in cumulative uterine activity following all the doses of oral misoprostol, compared with intramuscular syntometrine, the largest difference being seen in oral misoprostol 200 μg (adjusted mean difference –2282 kPas s, 95% CI –7954 to 3390 kPas s). The mean onset of action of oral misoprostol (6.1, SD 2.1 min) was significantly slower than that of intramuscular syntometrine (3.2, SD 1.5 min; P=0.002), but their durations of action were similar ( P=0.637). In the misoprostol group the commonest side effects were shivering (36%) and a rise in body temperature above 38°C (40%). In the syntometrine group, the most commonly observed side effect was moderate uterine pain (nine out of ten women) and a rise in diastolic blood pressure of 20 mmHg (two out of ten women). Conclusion The results of this study show that oral misoprostol has a definite uterotonic effect on the postpartum uterus. At doses of 200 μg to 400 μg, oral misoprostol has a similar uterotonic effect to intramuscular syntometrine. Higher doses of oral misoprostol are associated with significantly more side effects.

Postpartum intrauterine pressure studies of the uterotonic effect of oral misoprostol and intramuscular syntometrine.

To investigate the effect of oral misoprostol in dosages varying from 200 microg to 800 microg on postpartum uterine contractility and to establish their side effects. A prospective descriptive study. Fifty-seven women who delivered vaginally after spontaneous labours not requiring augmentation. Within 5 minutes of delivery of the placenta, a calibrated Gaeltec catheter with an intrauterine pressure transducer at its tip was inserted transcervically into the uterine cavity. Cumulative uterine activity was recorded for 30 minutes in each woman before administering the oral misoprostol tablets and continued for a further 90 minutes after its administration. Thus each woman acted as her own control regarding changes in uterine contractility. Uterine activity was recorded on a Sonicaid Meridian fetal monitor, which measures active contraction area automatically. The incidence of side effects was also recorded. There was no statistical difference (P = 0.887) in the adjusted mean difference in cumulative uterine activity following all the doses of oral misoprostol, compared with intramuscular syntometrine, the largest difference being seen in oral misoprostol 200 microg (adjusted mean difference -2282 kPas s, 95% CI -7954 to 3390 kPas s). The mean onset of action of oral misoprostol (6.1, SD 2.1 min) was significantly slower than that of intramuscular syntometrine (3.2, SD 1.5 min; P = 0.002), but their durations of action were similar (P = 0.637). In the misoprostol group the commonest side effects were shivering (36%) and a rise in body temperature above 38 degrees C (40%). In the syntometrine group, the most commonly observed side effect was moderate uterine pain (nine out of ten women) and a rise in diastolic blood pressure of 20 mmHg (two out of ten women). The results of this study show that oral misoprostol has a definite uterotonic effect on the postpartum uterus. At doses of 200 microg to 400 microg, oral misoprostol has a similar uterotonic effect to intramuscular syntometrine. Higher doses of oral misoprostol are associated with significantly more side effects.

Changes in Uterine Contractility After Ovulation: Differences Between Menstrual and IVF cycles

Objective: We observed that uterine contraction (UC) frequency is increased in IVF at the time of ET, which adversely affects IVF outcome (Fanchin et al. 98). This led us to compare UC frequency in menstrual and IVF cycles. Specifically, we questioned whether IVF was associated with an overall increase in UC frequency or, with normal end follicular phase values followed by lack of decrease after ovulation because of some resistance to the uteroquiescent effects of progesterone. To clarify this issue, we prospectively studied the changes in UC frequency occurring after ovulation in 6 women, during the menstrual cycle that preceded IVF and the IVF cycle itself.

Uterine contractility and blood flow are reflexively regulated by cutaneous afferent stimulation in anesthetized rats

The effects of cutaneous mechanical afferent stimulation of various skin areas on uterine contractility and blood flow were examined in anesthetized non-pregnant rats. The contractility of the uterus was measured by the balloon method in the uterus. The uterine blood flow was measured by laser Doppler flowmetry. Noxious pinching stimulation of the perineum for 1 min induced an abrupt contraction of the uterus during stimulation. Pinching of a hindpaw or perineum and innocuous brushing of the perineum for 1 min increased uterine blood flow. Stimulation of other skin areas produced no changes in uterine contractility or blood flow. Most uterine responses were abolished by severance of the pelvic nerves, which innervated the uterus. The activity of pelvic parasympathetic efferent nerves to the uterus increased following perineal pinching. All these cutaneous stimulation-induced responses of uterine contractility, blood flow and pelvic efferent nerve activity still existed, and were even augmented, after acute spinalization. These results indicate that cutaneous mechanical sensory stimulation can regulate uterine contractility and blood flow by a segmental spinal reflex mechanism via uterine parasympathetic efferent nerves.

Effects of xylazine on early bovine pregnancy

The effects of xylazine on early pregnancy in cattle were determined in 39 beef heifers in the first trimester of gestation. Fetal heart rate ( n = 13), maternal heart rate ( n = 8) and uterine contractility ( n = 13) were observed at 3 min before and 3, 10, 60 and 120 min after the administration of xylazine (20 mg i.v.). All heifers were examined for fetal heart beats 1 week after the administration of xylazine. There was a decrease ( P < 0.01) in fetal and maternal heart rate at 3 min after injection. The fetal heart rate returned to pretreatment values within 60 min, whereas maternal heart rate was still depressed at 120 min after treatment. Uterine contractility was markedly increased ( P < 0.001) at 3 min after xylazine administration, but returned to normal within 120 min. Fetal heart beats were observed in 38 of the 39 heifers 1 week after xylazine treatment. A second experiment was designed to assess the effects of increased uterine activity on fetal heart rate after the injection of oxytocin (20 IU i.v., n = 11), the PGF 2α analogue cloprostenol (500 μg i.v., n = 7), and the uterine relaxant clenbuterol (300 μg i.v., n = 11) administered together with xylazine (20 mg i.v.). Oxytocin and cloprostenol caused an increase ( P < 0.05) in uterine contractility, but no changes in fetal heart rate. The injection of xylazine with clenbuterol resulted in a shorter, less pronounced increase in uterine contractility and less depression of fetal heart rate than xylazine alone. It was concluded that the decrease in fetal heart rate observed after the administration of xylazine to the dam is most likely the result of a specific pattern of increased uterine contractility and/or α 2 − receptor-mediated vasoconstriction, resulting in reduced uterine blood flow and subsequent fetal hypoxia and bradycardia. The changes in uterine contractility and fetal heart rate caused by a single injection of 20 mg xylazine in heifers in the first trimester of gestation have no short-term adverse effects on pregnancy.

Are gap junctions necessary for cell-to-cell coupling of smooth muscle?: An update.

Earlier, it was questioned whether gap junctions (GJs) were necessary for cell-cell communication in smooth muscle, and GJs were not seen in some smooth muscles. We reexamined this question in the myometrium and in intestinal smooth muscle, in light of current knowledge of the presence and function of GJs. In the uterus, numerous studies show that an increase in GJ number is associated with the onset of delivery and is required for effective parturition. In all cases, this increase in GJ number and the changes in uterine contractility were correlated with increased electrical and metabolic coupling. Evidence for the much smaller, but detectable, degree of electrical coupling in the preterm uterus is explained by the small (but again detectable) number of GJs present. In the intestine, GJs are readily detected in the circular muscle layer but have not been described in the adjacent longitudinal layer. While our immunohistochemical studies failed to detect GJs in the longitudinal layer, this may not be adequate to prove their absence. Therefore, current knowledge of GJ number and function is adequate to explain cell-cell coupling in the uterus. Although it remains uncertain whether GJs are absent from the longitudinal muscle of the intestine, there is no definitive evidence that cell-cell coupling can occur by means other than GJs.

Uterine Contractility and Interaction between Prostaglandins and Antiprogestins Clinical Implications

It is generally believed that progesterone and PGF2 alpha are of major importance in the regulation of uterine contractility. The results summarized herein indicate that progesterone withdrawal is essential for the changes in uterine contractility normally observed during the secretory phase of the menstrual cycle and that the inactivity of the early pregnant uterus is progesterone dependent. Treatment with the antiprogestin RU486 will convert the inactive early pregnant uterus to an active organ and will increase the sensitivity of the myometrium to prostaglandin. These latter effects of antiprogestin have resulted in the development of highly effective, nonsurgical procedures to terminate early pregnancy based on a combined treatment with RU486 and different PG analogues administered orally, vaginally, or intramuscularly. RU486 also has a softening effect on the cervix as demonstrated in late first trimester of pregnancy. This effect may be useful as pretreatment to vacuum aspiration in late first and early second trimester abortion performed by vacuum aspiration or dilatation and curettage. In prostaglandin-induced second trimester abortions, pretreatment with RU486 will significantly reduce the induction-to-abortion interval and the dose of prostaglandin needed.

The effects of xylazine and alpha-adrenoreceptor antagonists on bovine uterine contractility in vitro

The effects of alpha-adrenoreceptor antagonists prazosin (alpha-1), yohimbine (alpha-2), and idazoxan (alpha-2) on xylazine-induced bovine uterine contractility were tested in vitro. Uterine strips from proestrous/estrous and diestrous cows were mounted in tissue baths containing Tyrode's solution. Changes in uterine contractility were measured by strain gauge. The following results were observed: 1) Xylazine increased uterine contractility in a dose dependent manner (cumulative concentrations: 10 −8, 3×10 −8, 10 −7, 3×10 −7 and 10 −6M). 2) Idazoxan (10 −8, 10 −7 and 10 −6M) and yohimbine (10 −6, 10 −5 and 10 −4M) antagonized uterine contractility induced by xylazine in a dose-dependent manner. Idazoxan was approximately 50 to 100 times more potent than yohimbine. 3) Prazosin (10 −5M) did not alter the effect of xylazine on uterine contractility. These results suggested that xylazine-induced uterine contractility in the cyclic cow is directly mediated by myometrial alpha-2 adrenoreceptors.

Uterine activity and placental histology in abortion at mid-trimester by rivanol and catheter.

Artificial abortions were performed on 7 patients during mid-pregnancy by intra-uterine instillation of 0.1% rivanol and catheters. The changes in uterine contractility during the treatment were monitored continuously by intra-amniotic pressure recording. Uterine activity developed a gradual but steady increase and abortion was completed within 22 to 47 hours. A significant increase in uterine contractility started after a lag of several hours. Neither hypertonus nor hyperactivity was noted during the treatment. The fetus was delivered unaffected in all cases. The placentas delivered showed normal histological integrity, and an autoradiographic study established the viability of trophoblasts. These results suggest that the abortive effect of rivanol and catheter on the uterus and placenta is different from that induced by other chemicals.

A study of uterine contractility in the toxemias of pregnancy

The present investigation was planned for the study of the changes in uterine contractility in the various pathological conditions that are usually associated with the clinical picture of toxemia: (1) pure pre-eclampsia, (2) chronic hypertension, (3) chronic renal disease, and (4) combinations of these conditions. Four groups of women representing these conditions were divided into groups at term and somewhat earlier and according to whether they were receiving parenteral antihypertensive therapy. Intra-amniotic pressure changes, maternal arterial blood pressure, and fetal heart rate were recorded in 64 patients. The fundamental abnormality of uterine contractility in pre-eclampsia and similar medical problems was found to be the early appearance of a pattern characteristic of more advanced stages of pregnancy. The contractions have a tendency to appear more often, but their intensity and the total uterine activity and the uterine tonus remain within normal ranges and uterine reactivity is lower than normal when more than 4 milliunits of oxytocin per minute are administered. This type of contractility seems to be the common pattern of premature labor whatever its cause and is not a behavior specifically characteristic of the uterus in the toxemias of pregnancy.

Metreurynter-induced abortions at midpregnancy: The changes in uterine contractility and in urinary output of pregnanediol and estrogen

Using 5 healthy women at midpregnancy and one case of intrauterine fetal death as material, metreurynter-induced abortions were performed, and the relationship between the increase in uterine contractility (as assessed on three indices, viz., frequency, intensity, and uterine activity), and the urinary excretion rate of pregnanediol and estrogen was studied. The placenta was also assessed after delivery. From metreurynter insertion to delivery, uterine contractility increased steadily, while the rate of urinary output of both hormones in any single patient did not decrease significantly. Histologically, there was no sign of acute placentitis except in the case of intrauterine fetal death, in which chronic placentitis and diffuse infarction were observed.